The present invention relates to certain compounds of the formula (I), depicted below, having utility as hypoglycemic and hypocholesteremic agents, methods for their use and pharmaceutical compositions containing them.
In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type I diabetes, insulin dependent diabetes mellitus), requires multiple daily doses, usually by self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and in more severe cases, insulin. However, the clinically available hypoglycemics are unfortunately fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may be less toxic or succeed where others fail, is clearly evident.
Furthermore, atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease has been described in detail by Ross and Glomset in New England Journal of Medicine 295, 369-377 (1976). The earliest stage in this sequence is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Cholesterol and cholesteryl ester account for most of this lipid. Further, it is postulated that most of the cholesterol found within the fatty streaks results from uptake from the plasma. These fatty streaks, in turn, give rise to development of the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the "complicated lesion" which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscular spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hypedipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of "normal" are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at high risk for development or progression of CVD because of this factor. Individuals who posses independent risk factors in addition to hypedipidemia are at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
The first step in recommended therapeutic regimens for hyperlipidemia is dietary intervention. While diet alone produces adequate response in some individuals, many others remain at high risk and must be treated further by pharmacological means. New drugs for the treatment of hyperlipidemia are, therefore, of great potential benefit for large numbers of individuals at high risk of developing CVD. Further, successful treatment of both the hyperlipidemia and hyperglycemia associated with the diabetic state with a single therapeutic agent is particularly desirable.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been reported to possess this type of activity, as reviewed by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080].
Schnur, U.S. Pat. No. 4,367,234 discloses hypoglycemic oxazolidinediones of the formula ##STR2## in which the phenyl ring is generally mono- or multi-substituted in the ortho/meta positions. Notably, with the exception of the 4-fluorophenyl analog, the para-substituted derivatives are either inactive or possess a low level of hypoglycemic activity. Schnur, U.S. Pat. Nos. 4,332,952 and 4,342,771 further disclose a variety of similar oxazolidinedione hypoglycemic agents which are alternatively substituted at the 5-position with a heterocyclic group. These include certain furan, thiophene, pyrrole and pyridine derivatives.
Schnur, U.S. Pat. No. 4,617,312 discloses hypoglycemic thiazolidinediones of the formula ##STR3## where R.sup.c is lower alkyl, X.sup.a is F, CI or Br, and Y.sup.a is hydrogen, chloro, lower alkyl or lower alkoxy. Notably, the compounds require ortho-substitution with an alkoxy group, and para-substitution is limited to hydrogen or halogen. Shoda et al. (Chem. Pharm. Bull., 30, 3563 (1982) describe the preparation of a series of 5-[4-(2-methyl-2-phenylpropoxy)benzyl]thiazolidine-2,4-diones as antidiabetic agents. Kawamatsu et al., U.S. Pat. No. 4,340,605, disclose hypoglycemic compounds of the formula ##STR4## wherein R.sup.c is a bond or lower alkylene and when R.sup.d is an optionally substituted five- or six-membered hetero-cyclic group including one or two hetero-atoms selected from N, O and S; L.sup.1 and L.sup.2 may each be defined as hydrogen.
Eggler et al., U.S. Pat. No. 4,703,052, discloses hypoglycemic thiazolidinediones of the formula ##STR5## where the dotted line represents an optional bond, R.sup.f is H, methyl or ethyl, X.sup.b is O, S, SO, SO.sub.2, CH.sub.2, CO, CHOH or NR.sup.k, R.sup.k is H or an acyl group and the numerous definitions of R.sup.g, R.sup.h, R.sup.i and R.sup.j as optionally substituted phenyl, benzyl, phenethyl or styryl.
Meguro et al., U.S. Pat. No. 4,725,610 disclose a sedes of hypoglycemic thiazolidinediones of the formula ##STR6##
EP 283,035A and EP 299,620A describe benzoxazole and benzofuran linked thiazolidinediones as antidiabetic agents,
EP 299,620A describes a compound of the formula: ##STR7## or a pharmaceutically acceptable salt thereof wherein A.sup.o represents nitrogen or a moiety R.sup.1 --C-- wherein
R.sup.1 represents hydrogen, alkyl or a substituted or unsubstituted aryl group; PA1 R.sup.2 represents a moiety R.sup.3 --Y--Z-- wherein R.sup.3 represents substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl or a substituted or unsubstituted oxazolyl group, and Y represents --(CH.sub.2).sub.n -- wherein n represents zero or any integer in the range of 1 to 6 and Z represents --CH.sub.2 --, --CH(OH)-- or --CO--; PA1 R.sup.a and R.sup.b each represent hydrogen or R.sup.a and R.sup.b together represent a bond; PA1 A represents a residue of a benzene ring, the carbon atoms of the residue having in total up to four substituents; and PA1 X represents O or S.
EP 299,620A encompasses the compounds of this invention in its broad generic disclosure; however, it does not describe or exemplify the compounds of the present invention, nor disclose how to make them. The compounds of the present invention show substantially greater hypoglycemic activity compared to the compounds of EP 299,620A.